Photomedicine and Laser Surgery
Volume 32, Number 11, 2014
ª Mary Ann Liebert, Inc.
Pp. 627–632
DOI: 10.1089/pho.2014.3805
Effects of Photodynamic Therapy with Blue Light
and Curcumin as Mouth Rinse for Oral Disinfection:
A Randomized Controlled Trial
Diego Portes Vieira Leite, DS,1,2 Fernanda Rossi Paolillo, PhD,2 Thiago Nogueira Parmesano,2
Carla Raquel Fontana, PhD,3 and Vanderlei Salvador Bagnato, PhD 2
Abstract
Objective: The purpose of this study was to evaluate the effects of the antimicrobial photodynamic therapy (aPDT) with blue light and curcumin on oral disinfection during the 2 h after treatment. Background data: a-PDT
is a technique that can potentially affect the viability of bacterial cells, with selective action targeting only areas
with photosensitizer accumulation. Materials and methods: A randomized controlled trial was undertaken.
Twenty-seven adults were randomly divided into three groups: (1) the PDT group, which was treated with the
drug, curcumin, and blue light (n = 9); (2) the light group, which was treated only with the blue light, and no
drug (n = 9) and; (3) the curcumin group, which was treated only with the drug, curcumin, and no light (n = 9).
The irradiation parameters were: blue light-emitting diode (LED) illumination (455 – 30 nm), 400 mW of average optical power, 5 min of application, illumination area of 0.6 cm2, 600 mW/cm2 of intensity, and 200 J/cm2
of fluence. A curcumin concentration of 30 mg/L was used. The saliva samples were collected for bacterial
counts at baseline and after the experimental phases (immediately after treatment, and 1 and 2 h after treatment).
Serial dilutions were performed, and the resulting samples were cultured on blood agar plates in microaerophilic
conditions. The number of colony-forming units (CFU) was determined. Results: The PDT group showed a
significant reduction of CFU immediately after treatment (post-treatment) with PDT (5.71 – 0.48, p = 0.001),
and 1 h (5.14 – 0.92, p = 0.001) and 2 h (5.35 – 0.76, p = 0.001) after treatment, compared with pretreatment
(6.61 – 0.82). There were no significant changes for the light group. The curcumin group showed a significant
increase of CFU 1 h after treatment (6.77 – 0.40, p = 0.02) compared with pretreatment (5.57 – 0.91) falling to
baseline values at 2 h after treatment (5.58 – 0.70). Conclusions: The PDT group showed significant difference
in microbial reduction ( p < 0.05) compared with both the light and curcumin groups until 2 h post-treatment.
The new blue LED device for PDT using curcumin may be used for reduction of salivary microorganisms,
leading to overall disinfection of the mouth (e.g., mucosa, tongue, and saliva), but new protocols should be
explored.
Introduction
T
he normal mouth has a large number of bacteria.
It results in increased risk of infection when many types
of surgical procedures are performed, mainly intraoral surgery. In these cases, prophylactic systemic antibiotics are
used, but these drugs may be associated with unfavorable side
effects. Oral antiseptics (for example, chlorhexidine) can also
be used in these cases, but the reduction of intraoral bacterial
counts is temporary.1 In this context, new procedures for oral
disinfection should be investigated.
1
2
3
Blue light (405–470 nm) without the addition of exogenous photosensitizers (PS) has intrinsic antimicrobial effect
and shows fewer deleterious effects to mammalian cells
than ultraviolet irradiation.2 According Soukos et al.,3 the
amount of endogenous porphyrin and/or other cell pigments
produced in Prevotella intermedia, Porphyromonas gingivalis, Prevotella melaninogenica, and Prevotella nigrescens
can explain a susceptibility to blue light resulting in oral
disinfection.
Moreover, curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)1,6-heptadiene-3,5,-dione] shows antimicrobial activity as
Department of Biomedical Engineering from University of Camilo Castelo Branco (UNICASTELO) São José dos Campos, SP, Brazil.
Optics Group from Physics Institute of São Carlos (IFSC), University of São Paulo (USP), São Carlos, SP, Brazil.
Department of Clinical Analysis, School of Pharmaceutical Sciences, Universidade Estadual Paulista (UNESP), Araraquara, SP, Brazil.
627
628
well. Curcumin is the principal yellow pigment isolated
from turmeric (Curcuma longa Linn).4 Several pharmacological properties of curcumin have been reported, such as
antioxidant and anti-inflammatory,4,5 antibacterial,6 antifungal,7 and anticarcinogenic5 effects, mainly with high
doses of curcumin alone.8 Because of the extended antimicrobial activity of curcumin and its safety assessed by
clinical trials in humans,9 it was used as a structural sample
to design the new antimicrobial agents with modified and
increased antimicrobial activities through the synthesis of
various derivatives related to curcumin.10 Moreover, curcumin-mediated antimicrobial photodynamic therapy (aPDT) can be used at low doses in combination with light
exposure, with considerable antibacterial effect. In this
context, curcumin has a rather broad absorption peak (range
300–500 nm), with a maximum absorption band at wavelength 430 nm, and it can be used as PS in a-PDT.11
PDT uses a nontoxic drug called a PS, which is activated
by exposure to light of a specific wavelength in the presence
of oxygen. This results in the production of reactive oxygen
species (ROS), which can potentially affect the viability of
bacterial cells with selective action targeting only areas with
PS accumulation.12,13 In this context, PDT has no side effects, and bacteria do not develop resistance to ROS.1
Several in vitro studies and clinical trials were performed
to investigate bactericidal action and oral disinfection using
blue light3,14,15 or curcumin,16,17 or by performing PDT with
blue light and curcumin.18–22 In dentistry, a-PDT may reduce both dental plaque and the risk of developing caries, as
well as contributing to treating gingivitis, periodontitis, periimplantitis and endodontic diseases.23
Previous clinical trials from our group have found that
PDT with blue light and curcumin significantly reduced
salivary microorganisms pre- and post-treatment.1 However,
oral disinfection as a function of time, to our knowledge, has
not been investigated. Therefore, the aim of this study was
to evaluate the effects of the PDT with blue light and curcumin on oral disinfection during 2 h after treatment. Our
target was overall oral flora (mucosa, tongue, saliva), conducting analyses of salivary pathogens before and after antimicrobial photodynamic therapy. Our hypothesis was that
blue light with or without curcumin, as well as only curcumin, could reduce colony-forming units (CFU).
LEITE ET AL.
and males between 20 and 35 years of age were randomly
divided into three groups: (1) the PDT group, which was
treated with the drug, curcumin, and blue light (n = 9); (2)
the light group, which was treated only with the blue light,
and no drug (n = 9); and (3) the curcumin group, which was
treated only with the drug, curcumin, and no light (n = 9).
Instrumentation to perform PDT
In order to perform PDT on the oral cavity, a device based
on blue light-emitting diode (LED) (455 – 30 nm) with
transparent acrylic diffuser tip and cylindrical shape (89 mm
length and 6.73 mm diameter) was developed by researchers
of the industry (MM Optics, São Carlos, SP, Brazil) and the
Optics Group of the Physics Institute of São Carlos (IFSC),
University of São Paulo (USP). An optical power meter
model FieldMaster TO-II (Coherent Inc., Santa Clara, CA)
linked to a photodetector was used to calibrate this device,
and to reveal a 400 mW average optical power, a 0.6 cm2
illumination area, and a 600 mW/cm2 intensity. The light
was applied for 5 min, which led to an energy density (radiation dose) delivered of *200 J/cm2. We considered a
total energy per unit of area reaching the surface as the
delivered dose, but this was not necessarily uniformly absorbed. The dose delivery was approximated, because different areas and several distances were irradiated. The new
blue LED device in the oral cavity can be seen in Fig. 1.
Although we applied the blue LED for 5 min as in the
clinical trial of Araújo and collaborators,1 the device
Materials and Methods
The current research has been approved by the Ethics
Committee of the Federal University of São Carlos (UFSCar) in São Carlos, Brazil (N. 258.461). The study was
registered with the National Institutes of Health (NIH)
ClinicalTrials (NCT02152475). All subjects signed written
informed consent forms before their participation in the
study.
A randomized controlled trial was undertaken. The inclusion criteria were healthy adults not using any antibiotic
therapy who did not perform any oral hygiene, such as
flossing, brushing, or use of antiseptic mouthwash, and who
had fasted for 12 h prior the treatment and measurements.
The exclusion criteria were having had oral cancer, smoking, pregnancy, or wearing partial or total dentures or orthodontic brackets. We performed simple randomization by
a computer program. Twenty-seven healthy adult females
FIG. 1. New blue light-emitting diode (LED) device for
photodynamic therapy (PDT) in the oral cavity.
BLUE LIGHT AND CURCUMIN
Table 1.
629
Effects of the Blue LED Illumination With or Without Curcumin
Pretreatment
PDT group
Light group
Curcumin group
6.61 – 0.82
5.67 – 0.82
5.57 – 0.91
Post-treatment
5.71 – 0.48
6.10 – 0.62
6.21 – 0.58
a
Post 1 h
Post 2 h
a
5.14 – 0.92
5.51 – 0.93
6.77 – 0.40a
5.35 – 0.76a
5.84 – 0.65
5.58 – 0.70b
Data represent the log10 CFU/mL.
a
Significant intragroup difference compared with pretreatment (two way ANOVA with post-hoc Tukey, p < 0.01).
b
Significant intragroup difference compared with period immediately before (two way ANOVA with post-hoc Tukey, p < 0.05).
LED, light-emitting diode; PDT, photodynamic therapy; CFU, colony-forming units.
geometry used in our study was different; therefore, the
parameters also were different.
Curcumin
A stock solution (1.5 g/L) of curcumin (PDT Pharma,
Cravinhos, SP, Brazil) was prepared in dimethylsulfoxide
(DMSO) (0.1%) and then diluted in autoclaved distilled
water (980 mL) to obtain the concentration used (30 mg/L).
The literature explores different concentrations.18–20,22 In
the clinical trial of Araújo and collaborators,1 the curcumin
salt used had 1 g of salt containing 0.654 g of the cucumin
plus curcuminoid, but in our study, natural curcumin (curcumin 53.4% and curcuminoid 46.16%) was used.
Treatment for oral disinfection
The volunteers in the PDT group used mouthwash with
20 mL of curcumin solution for 5 min, after which the solution was expelled and a blue light was introduced to activate the curcumin for 5 min. In the same way, the oral
cavity of the light group was illuminated with blue light for
5 min and the curcumin group used mouthwash with 20 mL
of curcumin solution for 5 min.1 We did not use similar
parameters of the blue illumination and curcumin concentration to those applied in in vitro studies, because in vivo
studies show complexity regarding variety of biological
tissues in the oral cavity and in immunological response.
levels: pretreatment, post-treatment, post 1 h, and post 2 h),
which was also considered a repeated measurement (intragroup differences). The survival fraction normalized
and the delta CFU between the situations before and after
the treatments (post-treatment, post 1 h, and post 2 h) was
performed for intergroup comparisons using a one-way
ANOVA with post-hoc Tukey tests. The Statistica for
Windows Release 7 software (Statsoft Inc., Tulsa, OK) was
used for the statistical analysis, and the significance level
was set at 5% ( p < 0.05).
Results
The PDT group showed a significant reduction in CFUs
(1 log reduction) at post-treatment, post 1 h, and post 2 h
( p < 0.01) compared with instance pretreatment. There were
no significant changes for the light group. The curcumin
group showed a significant increase in CFUs at post 1 h
( p < 0.05) compared with pretreatment, falling to baseline
values at post 2 h. These intragroup differences can be seen
in the Table 1. The PDT group showed a significant difference ( p < 0.05) in both normalized CFUs (Fig. 2) and
microbial reduction (Fig. 3) compared with both the light
and curcumin groups.
Discussion
The main finding of this study was that the PDT group
showed reduction in CFUs immediately post-treatment.
Microbiological analyses
Two saliva samples from each volunteer were collected at
each time point (pretreatment, post-treatment, post 1 h, and
post 2 h) and stored in sterile containers. The saliva samples
underwent serial dilutions and 100 lL aliquots were plated
on Brain Heart Infusion Agar (BHIA) with 10% Sheep
Blood (Difco Laboratories, Detroit, MI) plates (in duplicate)
and then incubated under microaerophilic conditions for
48 h at *36C. After incubation, the total number of CFUs
was determined.1
Statistical analysis
The data were expressed as means and standard deviations. In order to assess the effect of the treatments, CFU/mL
values were transformed to logarithm (log10). The Shapiro–
Wilk test was used to analyze data normality and the homogeneity of variances using Levene’s test. Two way
repeated measures ANOVA with post-hoc Tukey tests were
used to compare changes in CFUs as a function of time.
The independent factors were group (with three levels:
PDT, light, and curcumin groups) and time (with four
FIG. 2. Normalized colony-forming units (CFU). aSignificant intergroup difference compared with light group (one way
ANOVA with post-hoc Tukey, p < 0.05). bSignificant intergroup difference compared with curcumin group (one way
ANOVA with post-hoc Tukey, p < 0.01).
630
FIG. 3. Viable counts of colony-forming units (CFU)
between pretreatment and after treatment. Significant intergroup difference (one way ANOVA with post-hoc Tukey,
p < 0.05). The photodynamic therapy (PDT) group showed
significant microbial reduction compared with both the
lighta and curcuminb groups at pretreatment minus posttreatment ( p = 0.02 and p = 0.03), pretreatment minus post
1 h ( p = 0.01 and p = 0.04), and pretreatment minus post 2 h
( p = 0.04 and p = 0.03). The light group showed significant
difference compared with the curcuminb group ( p = 0.01).
Surprisingly, this antimicrobial effect was observed for 1 h
after PDT (*1 log reduction). These findings corroborate
study of Araújo et al.,1 which investigated the immediate
effects of PDT with blue light and curcumin in a clinical
trial. Other studies also showed the positive effects of
a-PDT. However, these studies used first and second generation photosensitizers such as porphyrin derivative,24
phthalocyanines,13 chlorine,25 toluidine blue,26 and methylene blue,27 which may target both gram-negative and grampositive bacteria.
Regarding a-PDT with curcumin and blue light, several
in vitro studies were performed. Dovigo et al.18,19 showed
that low curcumin concentrations were effective for inactivating Candida albicans when associated with blue LED
(450 nm) excitation. In similar studies, Araújo et al.22,28
found reduction of Streptococcus mutans and Lactobacillus
acidophilus on planktonic cultures,28 and this reduction was
more effective in biofilm compared with carious dentine
conditions.22 In a recent study, Pileggi et al.20 showed that
curcumin associated with a dental quartz-tungsten-halogen
light source, emitting blue light (380–500 nm) inactivated
Enterococcus faecalis on planktonic cultures or in biofilm
cultures. In another recent study, Panhóca et al.29 performed
PDT with blue LED and curcumin associated with surfactant (sodium dodecyl sulfate 0.1%), and showed inactivation
of S. mutans in biofilm, optimizing a-PDT. In the same line,
Paschoal et al.21 showed that a low concentration of curcumin associated with white light (400–700 nm with a
central wavelength of 550 nm) illumination lead to inactivation of S. mutans.
These results with regard to a-PDT are limited to an
in vitro model; however, they may support our clinical trial
results. Moreover, these in vitro model results also showed
that blue light irradiation alone or curcumin alone did not
reduce CFU.
LEITE ET AL.
Unlike other in vitro studies, the work of Lipovsky et al.30
showed bacterial reduction (Staphylococcus aureus and
Escherichia coli) with blue light (415 and 455 nm) alone,
mainly at higher fluences (120 J/cm2); however, at low fluences, blue light enhanced bacterial proliferation.31 In addition, Feuerstein et al.14 showed bacterial reduction (P.
gingivalis and Fusobacterium nucleaturn) with blue light
(450 nm) at fluences of 62, 78, and 94 J/cm2 under aerobic
condition; however, this phototoxic effect was not observed
when the bacteria were exposed to light under anaerobic
conditions. Considering blue LED applications, several
clinical trials for treatment of acne showed positive effects
of this wavelength.31,32 It is also evidenced by decrease
numbers of Propionibacterium acnes in vitro.32 Therefore,
the antibacterial effect of blue light is dose dependent as
well as dependent upon the response of an organism to O2 in
its environment.
Regarding use of curcumin alone, our study showed that
CFU increased significantly, suggesting that curcumin
probably caused disaggregation of dental plaque clumps on
tooth enamel leading to saliva. Curcumin has been tested as
a compound to inhibit fibril formation. Rabbie et al.33 observed disaggregation of preformed fibrils upon addition of
curcumin. Overall, this compound appears to be able to
interact with native, intermediate, and fibrillar forms.34,35
There is a fair amount of support from oral research to
suggest that bacteria fibrils are made of protein, and some
evidence that suggests that some are even made of glycoprotein. They are difficult to remove, and some strains of
oral streptococci have tufts of fibrils (that were grouped
together into a new species and given the name ‘‘Streptococcus cristae’’).36 There is evidence that fibril tufts and
coaggregation may also be involved in adhesion, this time to
rod-shaped bacteria, to make the structures commonly found
in mature dental plaque called ‘‘corncob-configuration.’’37
Considering the action on adhesion, our result in which
curcumin alone increased CFUs significantly, suggests that
this mouth rinse disrupts coaggregation bacteria attachment
to a tooth surface, leading bacteria to saliva. However,
several studies have shown that curcumin and other oral
disinfectants reduced CFU. Curcumin mouth rinse may be
dependent upon several factors, including duration of fasting28
and time of mouth rinse.38 Although there is a growing number
of publications about the effect of curcumin on bacterial reduction,16,18,28,39,41 few publications28,39 such as this study
observed the magnitude of curcumin as a mouth rinse.
In an in vitro model, Hegde and Kesaria17 showed that
curcumin reduced only C. albicans, and that sodium hypochlorite and neem (Azadirachta indica) were more effective
in microbial inactivation, because it reduced both E. faecalis
and C. albicans. In a clinical trial, Bhat et al.16 showed that
the antimicrobial efficacy of neem (3%) was highest, followed by cetylpyridinium chloride (0.5%), curcumin (5%),
and chlorhexidine gluconate (0.2%) when the CFU (S. mutans) reduction was measured. Chlorhexidine is widely used
in dentistry for decontamination. In the study by Hayek
et al.,41 Prevotella sp., Fusobacterium sp., and Streptococcus beta-haemolyticus were significantly reduced in
ligature-induced peri-implantitis in dogs; however, no significant differences were observed between chlorhexidine
and PDT with paste-based azulene and GaAlAs laser
(k = 660 nm).
BLUE LIGHT AND CURCUMIN
The action of curcumin alone as mouth rinse is quite
encouraging for a further development of the technique, as
prewash plaque remover and the reduction of 1 log for 2 h
after PDT is an excellent result, considering the advantages
of curcumin being a natural substance and harmless to the
oral tissues. Overall, decontamination using a simple procedure is desirable for general use in dentistry. In this
context, the reduction of bacterial counts and its maintenance
during 2 h are important for several intraoral surgical procedures during a single session. Moreover, bacterial reduction
is initiated on superficial surfaces of the oral environment,
and after multiples sessions of PDT, deeper layers can be
achieved. PDT is cumulatively bactericidal.42 However,
some limitations of our study were the small sample size per
group, and not having used different procedures for optimizing a-PDT. Future studies should explore these aspects.
Conclusions
In conclusion, in this study, the results indicate that curcumin has a potential to disaggregate oral plaque, and the
new blue LED device for PDT-curcumin may be used for
reduction of salivary microorganisms lasting 2 h, leading to
overall disinfection of the mouth for several intraoral surgical procedures during a single session of dentistry. However, new protocols should be explored to optimize a-PDT.
Acknowledgments
The authors thank the National Council for Scientific and
Technological Development (CNPq) - grant no. 573587/
2008 and the São Paulo Research Foundation (FAPESP) grant nos. 2013/07276-1 and 2013/14001-9 for financial
support. The authors also acknowledge scientific contributions
and helpful advice from Hérica Ricci and Vitor Hugo Panhóca.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Fernanda Rossi Paolillo
University of São Paulo (USP)
Av. Trabalhador Sãocarlense
400 – Centro, CEP 13560-970
São Carlos, SP
Brazil
E-mail: fer.nanda.rp@hotmail.com